Ortho-regioselective acylation

A further application of the metal-template effect in the ortho-regioselective acylation of phenols is represented by the direct synthesis of salicyloyl chloride and derivatives by the reaction of bromomagnesium phenolates 4 with phosgene. The reaction affords the unstable salicyloyl chloride-magnesium complexes 5 by a pathway similar to the mechanism depicted in Scheme 5.2. These intermediates can be in situ converted into the corresponding acids 6 (Scheme 5.3), esters, amides, or ketones by reaction with suitable reagents. 

Table 5.1 Ortho-regioselective acylation of phenoxymagnesium bromides with acyl chlorides...

From a synthetic point of view, the process can be efficiently applied to the preparation of a large variety of ortho-hydroxyaryl ketones, as summarized in Table 5.1. Results from Table 5.1 are a proof of the powerful metal-template effect in promoting ortho-regioselective electrophilic acylation of phenol substrates. 

Hoesch reaction. In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds (e.g., pyrrole), but it can be extended to aromatic amines by the use of BCls. Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones " but are attacked at the oxygen to produce imino esters. Many nitriles... 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.45 In general, para attack predominates for alkylbenzenes.46 The percentage of ortho attack increases with the electrophilicity of the acylium ion, and as much as 50% ortho product is observed with the formylium and... 

With arenes bearing a single resonance donor substituent (NR2, OMe, F), the addition is strongly preferred at the meta position, with small amounts of ortho substitution (0-10%). " The meta acylation of anisole, using a carbonyl anion equivalent as the nucleophile, illustrates the unique regioselectivity available with the Cr(CO)3 activation (equation 115). ... 

The Baeyer-Villiger reaction has solved a regioselectivity problem here. L-tyrosine, a relatively cheap amino acid, can be converted to the important drug L-dopa provided it can be hydroxylated ortho to the OH group. This is where electrophilic substitutions of the phenol take place, but electrophilic substitutions with HO are not possible. However, after a Friedel-Crafts acylation, the acyl group can be converted to hydroxyl by the Baeyer-Villiger reaction and hydrolysis. The Baeyer-ViUiger reaction means that MeCO can be used as a synthetic equivalent for Note... 

Deacylation." Removal of an entire acyl side chain from an aromatic ketone occurs when the acyl group is ortho to a potential ligand for ruthenium. Accordingly, this process exhibits excellent regioselectivity in the cases of certain diacylarenes. The importance of the coordination is shown by the fate of a p-(2-pyridyl)-a,p-unsaturated ketone. 

Treatment of a cyclic 2,3- or 3,4-ortho-ester in a pyranoside under mild acidic condititnis will cause regioselective cleavage so diat a free equatorial OH is poduced adjacmt to an axial 0-acyl group [14] (Scheme 1). The reasons for diis have engendered considerable theoretical treatment based on consideradons of stereoelectronic effects [15]. 

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